246 research outputs found

    Effects of typical and atypical antipsychotic drugs on gene expression profiles in the liver of schizophrenia subjects

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    <p>Abstract</p> <p>Background</p> <p>Although much progress has been made on antipsychotic drug development, precise mechanisms behind the action of typical and atypical antipsychotics are poorly understood.</p> <p>Methods</p> <p>We performed genome-wide expression profiling to study effects of typical antipsychotics and atypical antipsychotics in the postmortem liver of schizophrenia patients using microarrays (Affymetrix U133 plus2.0). We classified the subjects into typical antipsychotics (n = 24) or atypical antipsychotics (n = 26) based on their medication history, and compared gene expression profiles with unaffected controls (n = 34). We further analyzed individual antipsychotic effects on gene expression by sub-classifying the subjects into four major antipsychotic groups including haloperidol, phenothiazines, olanzapine and risperidone.</p> <p>Results</p> <p>Typical antipsychotics affected genes associated with nuclear protein, stress responses and phosphorylation, whereas atypical antipsychotics affected genes associated with golgi/endoplasmic reticulum and cytoplasm transport. Comparison between typical antipsychotics and atypical antipsychotics further identified genes associated with lipid metabolism and mitochondrial function. Analyses on individual antipsychotics revealed a set of genes (151 transcripts, FDR adjusted p < 0.05) that are differentially regulated by four antipsychotics, particularly by phenothiazines, in the liver of schizophrenia patients.</p> <p>Conclusion</p> <p>Typical antipsychotics and atypical antipsychotics affect different genes and biological function in the liver. Typical antipsychotic phenothiazines exert robust effects on gene expression in the liver that may lead to liver toxicity. The genes found in the current study may benefit antipsychotic drug development with better therapeutic and side effect profiles.</p

    Diversity of Plasmodium falciparum Chloroquine Resistance Transporter (pfcrt) Exon 2 Haplotypes in the Pacific from 1959 to 1979

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    Nearly one million deaths are attributed to malaria every year. Recent reports of multi-drug treatment failure of falciparum malaria underscore the need to understand the molecular basis of drug resistance. Multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) are involved in chloroquine resistance, but the evolution of complex haplotypes is not yet well understood. Using over 4,500 archival human serum specimens collected from 19 Pacific populations between 1959 and 1979, the period including and just prior to the appearance of chloroquine treatment failure in the Pacific, we PCR-amplified and sequenced a portion of the pfcrt exon 2 from 771 P. falciparum-infected individuals to explore the spatial and temporal variation in falciparum malaria prevalence and the evolution of chloroquine resistance. In the Pacific, the prevalence of P. falciparum varied considerably across ecological zones. On the island of New Guinea, the decreases in prevalence of P. falciparum in coastal, high-transmission areas over time were contrasted by the increase in prevalence during the same period in the highlands, where transmission was intermittent. We found 78 unique pfcrt haplotypes consisting of 34 amino acid substitutions and 28 synonymous mutations. More importantly, two pfcrt mutations (N75D and K76T) implicated in chloroquine resistance were present in parasites from New Hebrides (now Vanuatu) eight years before the first report of treatment failure. Our results also revealed unexpectedly high levels of genetic diversity in pfcrt exon 2 prior to the historical chloroquine resistance selective sweep, particularly in areas where disease burden was relatively low. In the Pacific, parasite genetic isolation, as well as host acquired immune status and genetic resistance to malaria, were important contributors to the evolution of chloroquine resistance in P. falciparum

    Isotopic methods for non-destructive assessment of carbon dynamics in shrublands under long-term climate change manipulation

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    1. Long-term climate change experiments are extremely valuable for studying ecosystem responses to environmental change. Examination of the vegetation and the soil should be non-destructive to guarantee long-term research. In this paper, we review field methods using isotope techniques for assessing carbon dynamics in the plant-soil-air continuum, based on recent field experience and examples from a European climate change manipulation network. 2. Eight European semi-natural shrubland ecosystems were exposed to warming and drought manipulations. One field site was additionally exposed to elevated atmospheric CO2. We evaluate the isotope methods that were used across the network to evaluate carbon fluxes and ecosystem responses, including: 1) analysis of the naturally rare isotopes of carbon (13C and 14C) and nitrogen (15N); 2) use of in-situ pulse labelling with 13CO2, soil injections of 13C- and 15N-enriched substrates, or continuous labelling by Free Air Carbon dioxide Enrichment (FACE) and 3) manipulation of isotopic composition of soil substrates (14C) in lab-based studies. 3. The natural 14C signature of soil respiration gave insight into a possible long-term shift in the partitioning between the decomposition of young and old soil carbon sources. Contrastingly, the stable isotopes 13C and 15N were used for shorter-term processes, as the residence time in a certain compartment of the stable isotope label signal is limited. The use of labelled carbon-compounds to study carbon mineralization by soil microorganisms enabled to determine the long-term effect of climate change on microbial carbon uptake kinetics and turnover. 4. Based on the experience with the experimental work, we provide recommendations for the application of the reviewed methods to study carbon fluxes in the plant-soil-air continuum in climate change experiments. 13C-labelling techniques exert minimal physical disturbances, however, the dilution of the applied isotopic signal can be challenging. In addition, the contamination of the field site with excess 13C or 14C can be a problem for subsequent natural abundance (14C and 13C) or label studies. The use of slight changes in carbon and nitrogen natural abundance does not present problems related to potential dilution or contamination risks, but the usefulness depends on the fractionation rate of the studied processes

    Olfactory discrimination predicts cognitive decline among community-dwelling older adults

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    The presence of olfactory dysfunction in individuals at higher risk of Alzheimer's disease has significant diagnostic and screening implications for preventive and ameliorative drug trials. Olfactory threshold, discrimination and identification can be reliably recorded in the early stages of neurodegenerative diseases. The current study has examined the ability of various olfactory functions in predicting cognitive decline in a community-dwelling sample. A group of 308 participants, aged 46–86 years old, were recruited for this study. After 3 years of follow-up, participants were divided into cognitively declined and non-declined groups based on their performance on a neuropsychological battery. Assessment of olfactory functions using the Sniffin' Sticks battery indicated that, contrary to previous findings, olfactory discrimination, but not olfactory identification, significantly predicted subsequent cognitive decline (odds ratio=0.869; P<0.05; 95% confidence interval=0.764−0.988). The current study findings confirm previously reported associations between olfactory and cognitive functions, and indicate that impairment in olfactory discrimination can predict future cognitive decline. These findings further our current understanding of the association between cognition and olfaction, and support olfactory assessment in screening those at higher risk of dementia
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